Toll-like receptors and their ligands control mesenchymal stem cell functions

Abstract

IntroductionMesenchymal stem cells (MSCs) comprise an adult population that resides in many organs and exhibits multiple functions and phenotypes upon in vitro culture; MSCs can be induced to differentiate into mesodermal cell lineages, 1,2 support and regulate hematopoiesis, [3][4][5][6][7] regulate the stem-cell niche, [8][9][10][11][12] and may participate in the repair of tissue damage inflicted by normal wear and tear, injury, or disease. [13][14][15][16] MSCs comprise 0.01% to 0.001% of the bone marrow (BM)-nucleated cells and are obtained by expansion of the BM, plastic-adherent cell fraction. 1,[17][18][19][20][21] Under certain physiologic or experimental conditions, MSCs can be induced to differentiate in vitro into cells of the mesodermal lineage, specifically to osteocytes, adipocytes, chondrocytes, myocytes, tenocytes, myocardiocytes, and hematopoietic supportive stroma. 1,17,19,22 MSCs are an attractive cell-based therapy tool for developmental defects; degenerating diseases; and bone, cartilage, muscle, and other mesodermal tissue injuries. [23][24][25][26][27][28][29][30] Toll-like receptors (TLRs) are a class of molecules first discovered to play a role in body development 31 and later found to play a role in body maintenance. [32][33][34][35][36] The TLR family has been shown to be of importance in the innate immune system for the recognition of pathogen-associated molecular patterns (PAMPs) by immune cells, initiating a primary response toward invading pathogens and recruitment of the adaptive immune response. 32,[37][38][39][40][41][42][43][44][45][46][47][48][49] TLRs can be activated not only by pathogen components, but also by mammalian endogenous molecules such as heat-shock proteins and extracellular matrix breakdown products. [50][51][52] In the steady state, during the generation of immune cells, as well as under pathologic conditions, there are intimate interactions between lymphocyte populations and the organ stroma mesenchyme. These interactions regulate cell growth and differentiation and control cell functions. It is possible therefore that lymphocytes and the stromal mesenchyme share regulatory mechanisms. To test this possibility we aimed, in the present study, to examine the expression and possible regulatory functions of TLRs in mesenchymal cells.We explored the expression of TLRs by MSCs, the response of MSCs to known TLR activators, and the ability of a TLR-2 ligand to regulate MSC proliferation and differentiation. We show here that cultured MSCs express TLR molecules 1 to 8, but not TLR-9. Activation of MSCs by TLR ligands induced interleukin-6 (IL-6) secretion and nuclear factor B (NF-B) nuclear translocation. Pam3Cys, a prototypic ligand for TLR-2, induced proliferation of MSCs and regulated their differentiation. Relatively little is known about the signals that regulate MSC proliferation, differentiation, and development. 53,54 Our findings suggest that TLR signaling may play a role in restraining MSC differentiation and thus promote MSC renewal. Materials and methods ...

Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…4A, 4C, and 6C). These results are in line with another study in mMSC [35]. As in human MSC [19], TLR3 and TLR4 are expressed at levels comparable to DC (Figs.…”

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

“…The low activation of NFkB detected in GICs suggests that NFkB may be dispensable for survival and proliferation of these tumor NFjB blockade promotes senescence of differentiating GICs L Nogueira et al progenitor cells, which correlates with data showing that p65 immunoreactivity is abundant in the cytoplasm of the majority of cells within neurospheres derived from embryonic mouse brain, but only occasional weak nuclear localization (active state) is detected (Young et al, 2006). NFkB has been described to function as an inducer and an inhibitor of differentiation, which reflects its heterogeneity in activities depending on the cell system studied (Zhang et al, 1998;Li and Makarov, 2006;Pevsner-Fischer et al, 2007;Vaira et al, 2008). We showed that blockade of NFkB by using genetic strategies or small-molecule inhibitors accelerate maturation of differentiating GICs.…”

Human Mesenchymal Stem Cell Therapy for Acute Graft Versus Host Disease

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